A recent ruling by the European Medicines Agency that the benefit-risk profile of Pfizer Inc.'s antidepressant Endronax (reboxetine) was positive contradicts the outcome of a similar assessment a year ago by German health technology assessment body IQWiG, which had rubbished the drug as “ineffective and potentially harmful.” But it’s far from clear that Pfizer will now have any chance to resurrect the drug in Germany, however.

IQWiG's conclusion led to the drug's being struck from the reimbursement list in Germany in September 2010, and came after months of accusations by the HTA body that Pfizer had chosen to make available only those studies supporting the drug.

The issue highlights the potential for conflict and confusion as national HTA bodies gain greater influence in Europe.

But EMA’s contrary Sept. 14 decision, based on a report carried out on its behalf by the U.K.'s Medicines and Healthcare products Regulatory Agency in response to potential risks flagged up by a pharmacovigiliance working party made up of a number of European countries, isn't binding across the European Union. So Germany could simply ignore it.

National HTA Agencies Have Louder Voices

More broadly, the issue highlights the potential for conflict and confusion as national HTA bodies gain greater influence in Europe. There's evidence of this increased influence in France, where the national medicines agency, AFSSAPS, suspended the marketing authorization of Takeda Pharmaceutical Co. Ltd.’s Actos (pioglitazone) in June following a joint exercise with the French health insurance system.

That action prompted Germany to recommend that no new patients should be treated with pioglitazone. Reactions from FDA and EMA were less extreme, however: FDA added a contraindication to the drug’s label within 48 hours of AFSSAPS’ suspension of the marketing authorization and EMA in July 2011 recommended the introduction of new contraindications and warnings for pioglitazone, but concluded that the “benefit-risk balance [of the drug] remains positive in a limited population of type 2 diabetics.”

France's suspension of Actos came amid a national health scandal that, at least from a political perspective, required visible, strong-fisted action against potentially dangerous drugs. The media furor around Servier's diabetes drug Mediator (benfluorex), allegedly linked to a series of deaths before its withdrawal in November 2009, triggered moves by the French authorities to demonstrate tighter control over benefit/risk assessment of drugs.

The Mediator affair has led to calls for increased cooperation between the national regulatory bodies (Servier voluntarily withdrew Mediator in Spain some six years before it was recalled in France) in order to minimize the risk of the same happening again (Also see "Mediator Scandal Provokes Flurry of French Health Reforms But Impact Is Hard To Gauge Until The Dust Settles" - Pink Sheet, 1 August, 2011.).

Indeed, France Health Minister Xavier Bertrand argued that the pioglitazone incident is evidence of increasing cooperation between worldwide regulatory agencies. That's certainly the aim of new EU pharmacovigilance regulations due to come into force in July 2012, which include more stringent reporting requirements. But Neil Grubert, an analyst at Decision Resources, reckoned that conflicts between EU medicines authorities could nevertheless become more common as they come under increased scrutiny at home and as political pressures of one kind or another lead them to react more cautiously than perhaps may be warranted on a purely scientific basis.

Going forward, manufacturers' own increased attention to risk-based issues, coupled with already-heavy scrutiny at EMA and national level agencies, plus mandatory risk-management plans around new drugs, should encourage faster and more harmonious/simultaneous reaction to safety signals.

Indeed, the safety issues that surrounded Pfizer’s Endronax were flagged up partly because it was an older drug and was not subject to the rigorous regulatory regimes of today. It may become rarer for the Pharmacovigilance Risk Assessment Committee (PRAC) – which will replace the Pharmacovigilance Working Party in 2012 – to escalate such issues as it seeks to avoid confrontation and adopt a more harmonious approach to risk assessment and minimization. Moreover, when conceiving the PRAC the European Commission was seeking a chance to enhance cooperation between the Member States and standardize practices.

New Trial Publication Rules in Germany May Resolve Data Access Issue

The conflicting conclusions on reboxetine ostensibly resulted from EMA's having taken into account more studies of the drug than IQWiG. EMA's report claims to have looked at all 11 of the placebo-controlled studies available with reboxetine, whereas IQWiG considered only seven. MHRA also argued that IQWiG’s investigation adopted an overall analysis approach, in which results were inconsistent between patient groups, whereas the European reviewers organized data by severity of disease. This discrepancy led the Germans to conclude that reboxetine was no more effective than placebo and was associated with higher safety risks, with Europeans claiming the drug was effective in patients with severe depression.

Since Germany's new drug assessment law, AMNOG, includes an obligation on manufacturers to publish all trial results – thereby potentially making this information available to assessment bodies worldwide – the data-access problem is unlikely to recur (Also see "Tweaks To German Pharma Law Require Firms to Prove Drugs' Value Within a Year" - Pink Sheet, 8 November, 2010.).

Indeed, the inclusion of such a requirement within AMNOG was a point scored for IQWiG, which, following its data-access tussle with Pfizer from 2008-2010, had called for the mandatory publication of all trial data, not only those that companies could manipulate to their advantage.

Since AMNOG came into force in January, companies must make available all trial data on a publicly accessible website, PharmNet.Bund, six months after authorization. If the medicine already is on the market, companies must publish information on additional clinical studies, following authorization, within one year. The information is made available in two formats: one for the general public and another for medical professionals.

AMNOG also protects IQWiG's powers within the framework of the new assessment procedure for drugs in Germany, which sees all new products go under the spotlight within a year, risking price curbs unless they show significant differentiation relative to standard of care.

IQWiG may not have the clout and scope of the UK's National Institute of Health and Clinical Excellence, but the law envisages that it will normally carry out drug assessments, if under delegation from Germany's senior HTA agency, the G-BA. For manufacturers, the only saving grace is that successive federal health ministers have stressed that AMNOG is a “living law,” open to updates in accordance with changing market conditions.

IQWiG May Rile Industry, But It Has Influence

Regarding reboxetine, IQWiG spokeswoman Anna-Sabine Ernst said that the HTA body would scrutinize the EMA document before taking any decisions to change or reverse its advice. It's possible – although unlikely – that the issue may be escalated to the EMA’s Committee for Medicinal Products for Human Use, which could, with European Commission sanction, issue a final decision that would be binding across the EU.

Pfizer could apply to IQWiG for a re-assessment of the cost-benefit analysis, suggested Peter Bogaert, managing partner at the international law firm Covington and Burling’s Brussels office. “There may also be openings for a legal action, including by patients,” he added. But it's already too little too late for Pfizer, with the drug over a decade old.

The latest flare-up between industry and IQWiG is nothing new. In 2009, IQWiG claimed that long-acting insulins were not superior to human insulin in long-term outcomes in people with type 2 diabetes, irking, among others, Sanofi and Novo Nordisk AS. More recently, an article published in the British Medical Journal referenced these findings in a study, which concluded that, while insulin analogs offered a modest benefit, the vast price differential between them and human insulin made them too costly for the U.K. NHS. The reference also points to the fact that, while IQWiG may not enjoy the same status as NICE, it is clearly still influential.

IQWiG’s last head, Peter Sawicki, was widely criticized as positioning himself as an anti-industry crusader with his own political agenda ([A#100311]). Sawicki was forced out of the position following the election of a new center-right government in October 2010. The new head, Jürgen Windele, is also viewed as taking a relatively hard line against the industry – though this is perhaps inevitable given the nature of any HTA agency's activities.

By Faraz Kermani

EU Regulators Contradict Germany's Assessment Of Pfizer Anti-Depressant

More from Europe

More from Geography